Biallelic IARS Mutations Cause Growth Retardation with Prenatal Onset, Intellectual Disability, Muscular Hypotonia, and Infantile Hepatopathy

Am J Hum Genet. 2016 Aug 4;99(2):414-22. doi: 10.1016/j.ajhg.2016.05.027. Epub 2016 Jul 14.

Abstract

tRNA synthetase deficiencies are a growing group of genetic diseases associated with tissue-specific, mostly neurological, phenotypes. In cattle, cytosolic isoleucyl-tRNA synthetase (IARS) missense mutations cause hereditary weak calf syndrome. Exome sequencing in three unrelated individuals with severe prenatal-onset growth retardation, intellectual disability, and muscular hypotonia revealed biallelic mutations in IARS. Studies in yeast confirmed the pathogenicity of identified mutations. Two of the individuals had infantile hepatopathy with fibrosis and steatosis, leading in one to liver failure in the course of infections. Zinc deficiency was present in all affected individuals and supplementation with zinc showed a beneficial effect on growth in one.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Alleles*
  • Animals
  • Child
  • Child, Preschool
  • Dietary Supplements
  • Fatty Liver / genetics
  • Female
  • Fetal Growth Retardation / genetics*
  • Fibrosis / genetics
  • Humans
  • Infant
  • Infant, Newborn
  • Intellectual Disability / genetics*
  • Isoleucine-tRNA Ligase / deficiency
  • Isoleucine-tRNA Ligase / genetics*
  • Liver Diseases / congenital*
  • Liver Diseases / genetics*
  • Liver Failure / genetics
  • Male
  • Muscle Hypotonia / congenital*
  • Muscle Hypotonia / genetics*
  • Mutation*
  • Syndrome
  • Zebrafish / genetics
  • Zinc / administration & dosage
  • Zinc / deficiency
  • Zinc / therapeutic use

Substances

  • Isoleucine-tRNA Ligase
  • Zinc